Browsing by Author "Buckley, Rachel"

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    Genetic variants and functional pathways associated with resilience to Alzheimer’s disease
    (Oxford, 2020-08-25) Dumitrescu, Logan; Mahoney, Emily R; Mukherjee, Shubhabrata; Lee, Michael L; Bush, William S; Engelman, Corinne D; Lu, Qiongshi; Fardo, David W; Trittschuh, Emily H; Mez, Jesse; Kaczorowski, Catherine; Hernandez Saucedo, Hector; Widaman, Keith F; Buckley, Rachel; Properzi, Michael; Mormino, Elizabeth; Yang, Hyun-Sik; Harrison, Tessa; Hedden, Trey; Nho, Kwangsik; Andrews, Shea J; Tommet, Doug; Hadad, Niran; Sanders, R Elizabeth; Ruderfer, Douglas M; Gifford, Katherine A; Moore, Annah M; Cambronero, Francis; Zhong, Xiaoyuan; Raghavan, Neha S.; Vardarajan, Badri; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Cruchaga, Carlos; Schellenberg, Gerard; Cox, Nancy J.; Haines, Jonathan L,; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Bennett, David A.; Schneider, Julie A.; Crane, Paul K.; Jefferson, Angela L.; Hohman, Timothy J.; Radiology and Imaging Sciences, School of Medicine
    Approximately 30% of older adults exhibit the neuropathological features of Alzheimer’s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer’s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10−20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10−4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer’s disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer’s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.
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    Implementation of Subjective Cognitive Decline criteria in research studies
    (Elsevier, 2017-03) Molinuevo, José L; Rabin, Laura A.; Amariglio, Rebecca; Buckley, Rachel; Dubois, Bruno; Ellis, Kathryn A.; Ewers, Michael; Hampel, Harald; Klöppel, Stefan; Rami, Lorena; Reisberg, Barry; Saykin, Andrew J.; Sikkes, Sietske; Smart, Colette M.; Snitz, Beth E.; Sperling, Reisa; van der Flier, Wiesje M.; Wagner, Michael; Jessen, Frank; Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION Subjective Cognitive Decline (SCD) manifesting prior to clinical impairment could serve as a target population for early intervention trials in Alzheimer’s disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed. METHODS Members of the SCD-I met to identify and agree upon topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly. RESULTS Topics included SCD inclusion and exclusion criteria, together with the informant’s role in defining SCD presence and the impact of demographic factors. DISCUSSION Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies.
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    Subjective cognitive decline and rates of incident Alzheimer's disease and non-Alzheimer's disease dementia
    (Elsevier, 2019-03) Slot, Rosalinde E. R.; Sikkes, Sietske A. M.; Berkhof, Johannes; Brodaty, Henry; Buckley, Rachel; Cavedo, Enrica; Dardiotis, Efthimios; Guillo-Benarous, Francoise; Hampel, Harald; Kochan, Nicole A.; Lista, Simone; Luck, Tobias; Maruff, Paul; Molinuevo, José Luis; Kornhuber, Johannes; Reisberg, Barry; Riedel-Heller, Steffi G.; Risacher, Shannon L.; Roehr, Susanne; Sachdev, Perminder S.; Scarmeas, Nikolaos; Scheltens, Philip; Shulman, Melanie B.; Saykin, Andrew J.; Verfaillie, Sander C. J.; Visser, Pieter Jelle; Vos, Stephanie J. B.; Wagner, Michael; Wolfsgruber, Steffen; Jessen, Frank; Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.